Cymbalta

Medical Editor: John P. Cunha, DO, FACOEP Last updated on RxList: 1/25/2022
Cymbalta Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

What Is Cymbalta?

Cymbalta (duloxetine) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for treating depression, anxiety disorder, and pain associated with diabetic peripheral neuropathy or fibromyalgia.

What Are Side Effects of Cymbalta?

Common side effects of Cymbalta include:

  • nausea,
  • dry mouth,
  • constipation,
  • diarrhea,
  • fatigue,
  • tired feeling,
  • drowsiness,
  • difficulty sleeping,
  • loss of appetite, and
  • dizziness.

Some patients may experience withdrawal reactions such anxiety, nausea, nervousness, and insomnia.

Dosage for Cymbalta

The recommended dose of Cymbalta for treating depression is 20 or 30 mg twice daily or 60 mg once daily. Cymbalta may interact with any medicine for pain, arthritis, fever, or swelling, including aspirin, ibuprofen, naproxen, celecoxib, diclofenac, indomethacin, piroxicam, nabumetone, etodolac, and others.

What Drugs, Substances, or Supplements Interact with Cymbalta?

Cymbalta may also interact with other drugs that make you sleepy or slow your breathing (sleeping pills, narcotics, muscle relaxers, or medicines for anxiety, depression, or seizures), blood thinner, buspirone, cimetidine, diuretics (water pills), fentanyl, lithium, St. John's wort, tramadol, tryptophan, some antibiotics, triptans for migraine, or other antidepressants.

Cymbalta During Pregnancy and Breastfeeding

Tell your doctor all medications and supplements you use. Tell your doctor if you are pregnant or plan to become pregnant while using Cymbalta; it is unknown if it will harm a fetus. Cymbalta may cause problems in a newborn if you take it during the third trimester of pregnancy. If you are pregnant, your name may be listed on a pregnancy registry to track the outcome of the pregnancy and to evaluate any effects of Cymbalta on the baby. Cymbalta passes into breast milk and may harm a nursing baby. Breastfeeding while taking Cymbalta is not recommended.

Additional Information

Our Cymbalta Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

QUESTION

What characterizes fibromyalgia? See Answer
Cymbalta Consumer Information

Get emergency medical help if you have signs of an allergic reaction (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have:

  • pounding heartbeats or fluttering in your chest;
  • a light-headed feeling, like you might pass out;
  • easy bruising, unusual bleeding;
  • vision changes;
  • painful or difficult urination;
  • impotence, sexual problems;
  • liver problems--right-sided upper stomach pain, itching, dark urine, jaundice (yellowing of the skin or eyes);
  • low blood sodium--headache, confusion, problems with thinking or memory, weakness, feeling unsteady; or
  • manic episodes--racing thoughts, increased energy, decreased need for sleep, risk-taking behavior, being agitated or talkative.

Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea.

Common side effects may include:

  • drowsiness;
  • nausea, constipation, loss of appetite;
  • dry mouth; or
  • increased sweating.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Cymbalta (Duloxetine Hcl)

SLIDESHOW

Fibromyalgia Symptoms, Diagnosis & Treatment See Slideshow
Cymbalta Professional Information

SIDE EFFECTS

The following serious adverse reactions are described below and elsewhere in the labeling:

  • Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see BOX WARNING and WARNINGS AND PRECAUTIONS]
  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
  • Orthostatic Hypotension, Falls and Syncope [see WARNINGS AND PRECAUTIONS]
  • Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]
  • Increased Risk of Bleeding [see WARNINGS AND PRECAUTIONS]
  • Severe Skin Reactions [see WARNINGS AND PRECAUTIONS]
  • Discontinuation Syndrome [see WARNINGS AND PRECAUTIONS]
  • Activation of Mania/Hypomania [see WARNINGS AND PRECAUTIONS]
  • Angle-Closure Glaucoma [see WARNINGS AND PRECAUTIONS]
  • Seizures [see WARNINGS AND PRECAUTIONS]
  • Increases in Blood Pressure [see WARNINGS AND PRECAUTIONS]
  • Clinically Important Drug Interactions [see WARNINGS AND PRECAUTIONS]
  • Hyponatremia [see WARNINGS AND PRECAUTIONS]
  • Urinary Hesitation and Retention [see WARNINGS AND PRECAUTIONS]
  • Sexual Dysfunction [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, one treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Reactions In Adults

Adult Clinical Trial Database

The data described below reflect exposure to CYMBALTA in placebo-controlled adult trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The age range in this pooled population was 17 to 89 years of age. In this pooled population, 66%, 61%, 61%, 43%, and 94% of adult patients were female; and 82%, 73%, 85%, 74%, and 86% of adult patients were Caucasian in the MDD, GAD, OA and CLBP, DPNP, and FM populations, respectively. Most patients received CYMBALTA dosages of a total of 60 to 120 mg per day [see Clinical Studies]. The data below do not include results of the trial that evaluated the efficacy of CYMBALTA for the treatment of GAD in patients ≥65 years old (Study GAD-5) [see Clinical Studies]; however, the adverse reactions observed in this geriatric population were generally similar to adverse reactions in the overall adult population.

Adverse Reactions Leading to Treatment Discontinuation in Adult Placebo-Controlled Trials

Major Depressive Disorder

Approximately 8.4% (319/3779) of CYMBALTA-treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of placebo-treated patients. Nausea (CYMBALTA 1.1%, placebo 0.4%) was the only adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the CYMBALTA-treated patients and at a rate of at least twice that of placebo-treated patients).

Generalized Anxiety Disorder

Approximately 13.7% (139/1018) of the CYMBALTA-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 3.3%, placebo 0.4%), and dizziness (CYMBALTA 1.3%, placebo 0.4%).

Diabetic Peripheral Neuropathic Pain

Approximately 12.9% (117/906) of the CYMBALTA-treated patients in placebo-controlled adult trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 3.5%, placebo 0.7%), dizziness (CYMBALTA 1.2%, placebo 0.4%), and somnolence (CYMBALTA 1.1%, placebo 0%).

Fibromyalgia

Approximately 17.5% (227/1294) of the CYMBALTA-treated patients in 3-to 6-month placebo-controlled adult trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 2.0%, placebo 0.5%), headache (CYMBALTA 1.2%, placebo 0.3%), somnolence (CYMBALTA 1.1%, placebo 0%), and fatigue (CYMBALTA 1.1%, placebo 0.1%).

Chronic Pain Due To Osteoarthritis

Approximately 15.7% (79/503) of the CYMBALTA-treated patients in 13-week, placebo-controlled adult trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 2.2%, placebo 1%).

Chronic Low Back Pain

Approximately 16.5% (99/600) of the CYMBALTA-treated patients in 13-week, placebo-controlled adult trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 3%, placebo 0.7%), and somnolence (CYMBALTA 1%, placebo 0%).

Most Common Adverse Reactions In Adult Trials

The most commonly observed adverse reactions in CYMBALTA-treated patients (as defined above) were:

  • Diabetic Peripheral Neuropathic Pain: nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.
  • Fibromyalgia: nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.
  • Chronic Pain due to Osteoarthritis: nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.
  • Chronic Low Back Pain: nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.

The most commonly observed adverse reactions in CYMBALTA-treated patients in all the pooled adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) (incidence of at least 5% and at least twice the incidence in placebo-treated patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.

Table 2 displays the incidence of adverse reactions in placebo-controlled trials for approved adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) that occurred in 5% or more of CYMBALTA-treated patients and with an incidence greater than placebo-treated patients.

Table 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Adult Populationsa

Adverse Reaction Percentage of Patients Reporting Reaction
CYMBALTA
(N=8100)
Placebo
(N=5655)
Nauseac 23 8
Headache 14 12
Dry mouth 13 5
Somnolencee 10 3
Fatigueb,c 9 5
Insomniad 9 5
Constipationcc 9 4
Dizzinessc 9 5
Diarrhea 9 6
Decreased appetitec 7 2
Hyperhidrosisc 6 1
Abdominal painf 5 4
a Includes adults with MDD, GAD, DPNP, FM, and chronic musculoskeletal pain. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.
b Also includes asthenia.
c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration.
d Also includes initial insomnia, middle insomnia, and early morning awakening.
e Also includes hypersomnia and sedation.
f Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain.

Adverse Reactions in Pooled MDD and GAD Trials in Adults
Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled adult trials that occurred in 2% or more of CYMBALTA-treated patients and with an incidence greater than placebo-treated patients.

Table 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo- Controlled Trials in Adultsa,b

System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction
CYMBALTA
(N=4797)
Placebo
(N=3303)
Cardiac Disorders
Palpitations 2 1
Eye Disorders
Vision blurred 3 1
Gastrointestinal Disorders
Nauseac 23 8
Dry mouth 14 6
Constipationc 9 4
Diarrhea 9 6
Abdominal paind 5 4
Vomiting 4 2
General Disorders and Administration Site Conditions
Fatiguee 9 5
Metabolism and Nutrition Disorders
Decreased appetitec 6 2
Nervous System Disorders
Headache 14 14
Dizzinessc 9 5
Somnolencef 9 3
Tremor 3 1
Psychiatric Disorders
Insomniag 9 5
Agitationh 4 2
Anxiety 3 2
Reproductive System and Breast Disorders
Erectile dysfunction 4 1
Ejaculation delayedc 2 1
Libido decreasedi 3 1
Orgasm abnormalj 2 <1
Respiratory, Thoracic, and Mediastinal Disorders
Yawning 2 <1
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis 6 2
aThe inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.
b For GAD, there were no adverse reactions that were significantly different between treatments in adults ≥65 years that were also not significant in the adults <65 years.
c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration.
d Includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain.
e Includes asthenia.
f Includes hypersomnia and sedation.
g Includes initial insomnia, middle insomnia, and early morning awakening.
h Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity.
i Includes loss of libido.
j Includes anorgasmia.

Adverse Reactions in the DPNP, FM, OA, and CLBP Adult Trials

Table 4 displays the incidence of adverse reactions that occurred in 2% or more of CYMBALTA-treated patients (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients.

Table 4: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trialsa

System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction
CYMBALTA
(N=3303)
Placebo
(N=2352)
Gastrointestinal Disorders
Nausea 23 7
Dry Mouthb 11 3
Constipationb 10 3
Diarrhea 9 5
Abdominal Painc 5 4
Vomiting 3 2
`Dyspepsia 2 1
General Disorders and Administration Site Conditions
Fatigued 11 5
Infections and Infestations
Nasopharyngitis 4 4
Upper Respiratory Tract Infection 3 3
Influenza 2 2
Metabolism and Nutrition Disorders
Decreased Appetiteb 8 1
Musculoskeletal and Connective Tissue
Musculoskeletal Paine 3 3
Muscle Spasms 2 2
Nervous System Disorders
Headache 13 8
Somnolenceb,f 11 3
Dizziness 9 5
Paraesthesiag 2 2
Tremorb 2 <1
Psychiatric Disorders
Insomniab,h 10 5
Agitationi 3 1
Reproductive System and Breast Disorders
Erectile Dysfunctionb 4 <1
Ejaculation Disorderj 2 <1
Respiratory, Thoracic, and Mediastinal Disorders
Cough 2 2
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis 6 1
Vascular Disorders
Flushingk 3 1
Blood pressure increasedl 2 1
aThe inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.
bIncidence of 120 mg/day is significantly greater than the incidence for 60 mg/day.
cIncludes abdominal discomfort, lower abdominal pain, upper abdominal pain, abdominal tenderness and gastrointestinal pain.
dIncludes asthenia.
eIncludes myalgia and neck pain.
fIncludes hypersomnia and sedation.
gIncludes hypoaesthesia, facial hypoaesthesia, genital hypoaesthesia and oral paraesthesia.
hIncludes initial insomnia, middle insomnia, and early morning awakening.
iIncludes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity.
jIncludes ejaculation failure.
kIncludes hot flush.
lIncludes increased diastolic blood pressure, increased systolic blood pressure, diastolic hypertension, essential hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary hypertension, and systolic hypertension.

Effects On Male And Female Sexual Function In Adults With MDD

Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual adverse reactions, was used prospectively in 4 MDD placebo-controlled adult trials (Studies MDD-1, MDD-2, MDD-3, and MDD-4) [see Clinical Studies]. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. Positive numbers signify a worsening of sexual function from baseline. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients.

In these trials, CYMBALTA-treated male patients experienced significantly more sexual dysfunction, as measured by the total score on the ASEX and the ability to reach orgasm, than placebo-treated male patients (see Table 5). CYMBALTA-treated female patients did not experience more sexual dysfunction than placebo-treated female patients as measured by ASEX total score. Healthcare providers should routinely inquire about possible sexual adverse reactions in CYMBALTA-treated patients.

Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Adult Trials

Male Patientsa Female Patientsa
CYMBALTA
(n=175)
Placebo
(n=83)
CYMBALTA
(n=241)
Placebo
(n=126)
ASEX Total (Items 1-5) 0.56b -1.07 -1.15 -1.07
Item 1 - Sex drive -0.07 -0.12 -0.32 -0.24
Item 2 - Arousal 0.01 -0.26 -0.21 -0.18
Item 3 - Ability to achieve erection (men); 0.03 -0.25 -0.17 -0.18
Lubrication (women) Item 4 - Ease of reaching orgasm 0.40c -0.24 -0.09 -0.13
Item 5 - Orgasm satisfaction 0. 09 0. 13 0. 11 0. 17
a n=Number of patients with non-missing change score for ASEX total.
b p=0.013 versus placebo.
cp<0.001 versus placebo.

Vital Sign Changes In Adults

In placebo-controlled clinical trials across approved adult populations for change from baseline to endpoint, CYMBALTA-treated patients had mean increases of 0.23 mm Hg in systolic blood pressure (SBP) and 0.73 mm Hg in diastolic blood pressure (DBP) compared to mean decreases of 1.09 mm Hg in SBP and 0.55 mm Hg in DBP in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see WARNINGS AND PRECAUTIONS].

CYMBALTA treatment, for up to 26 weeks in placebo-controlled trials across approved adult populations, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in CYMBALTA-treated patients, decrease of 0.17 beats per minute in placebo-treated patients).

Laboratory Changes In Adults

CYMBALTA treatment in placebo-controlled clinical trials across approved adult populations, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in CYMBALTA-treated patients when compared with placebo-treated patients [see WARNINGS AND PRECAUTIONS]. High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in CYMBALTA-treated patients compared to placebo-treated patients.

Other Adverse Reactions Observed During The Clinical Trial Evaluation Of CYMBALTA In Adults

Following is a list of adverse reactions reported by patients treated with CYMBALTA in clinical adult trials. In clinical trials of all approved adult populations, 34,756 patients were treated with CYMBALTA. Of these, 27% (9337) took CYMBALTA for at least 6 months, and 12% (4317) took CYMBALTA for at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

  • Cardiac Disorders - Frequent: palpitations; Infrequent: myocardial infarction, tachycardia, and Takotsubo cardiomyopathy.
  • Ear and Labyrinth Disorders - Frequent: vertigo; Infrequent: ear pain and tinnitus.
  • Endocrine Disorders - Infrequent: hypothyroidism.
  • Eye Disorders - Frequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment.
  • Gastrointestinal Disorders - Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer.
  • General Disorders and Administration Site Conditions - Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.
  • Infections and Infestations - Infrequent: gastroenteritis and laryngitis.
  • Investigations - Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased.
  • Metabolism and Nutrition Disorders - Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia.
  • Musculoskeletal and Connective Tissue Disorders - Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching.
  • Nervous System Disorders - Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria.
  • Psychiatric Disorders - Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide.
  • Renal and Urinary Disorders - Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.
  • Reproductive System and Breast Disorders - Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder.
  • Respiratory, Thoracic and Mediastinal Disorders - Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness.
  • Skin and Subcutaneous Tissue Disorders - Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis.
  • Vascular Disorders - Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.

Adverse Reactions Observed In Placebo-Controlled Clinical Trials In Pediatric Patients

Pediatric Clinical Trial Database

The data described below reflect exposure to CYMBALTA (N=567) in pediatric patients aged 7 to 18 years of age from two 10-week, placebo-controlled trials in patients with MDD (N=341) (Studies MDD-6 and MDD-7), one 10-week placebo-controlled trial in GAD (N=135) (Study GAD-6), and a 13-week trial in fibromyalgia (N=91). CYMBALTA is not approved for the treatment of MDD in pediatric patients [see Use In Specific Populations]. Of the CYMBALTA-treated patients in these studies, 36% were 7 to 11 years of age (64% were between 12 to 18 years old), 55% were female, and 69% were Caucasian. Patients received 30 to 120 mg of CYMBALTA per day during placebo-controlled acute treatment studies. In the pediatric MDD, GAD, and fibromyalgia trials up to 40 weeks long, there were 988 CYMBALTA-treated pediatric patients aged 7 to 17 years of age (most patients received 30-120 mg per day) – 35% were 7 to 11 years of age (65% were 12 to 17 years old) and 56% were female.

Most Common Adverse Reactions in Pediatric Trials

The most common adverse reactions (≥5% in CYMBALTA-treated patients and at least twice the incidence of placebo-treated patients) in all pooled pediatric populations (MDD, GAD, and fibromyalgia) were decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea.

Adverse Reactions in Pediatric Patients Aged 7 to 17 Years Old with MDD and GAD

The adverse reaction profile observed in clinical trials in pediatric patients aged 7 to 18 years old with MDD and GAD was consistent with the adverse reaction profile observed in adult clinical trials. The most common (≥5% and twice placebo) adverse reactions observed in these pediatric clinical trials included: nausea, diarrhea, decreased weight, and dizziness.

Table 6 provides the incidence of adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with CYMBALTA and with an incidence greater than patients treated with placebo. CYMBALTA is not approved in the treatment of MDD in pediatric patients [see Use In Specific Populations].

Table 6: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in Three 10-week Pediatric Placebo-Controlled Trials in MDD and GADa

System Organ Class/Adverse Reaction Percentage of Pediatric Patients Reporting Reaction
CYMBALTA
(N=476)
Placebo
(N=362)
Gastrointestinal Disorders
Nausea 18 8
Abdominal Painb 13 10
Vomiting 9 4
Diarrhea 6 3
Dry Mouth 2 1
General Disorders and Administration Site Conditions
Fatiguec 7 5
Investigations
Decreased Weightd 14 6
Metabolism and Nutrition Disorders
Decreased Appetite 10 5
Nervous System Disorders
Headache 18 13
Somnolencee 11 6
Dizziness 8 4
Psychiatric Disorders
Insomniaf 7 4
Respiratory, Thoracic, and Mediastinal Disorders
Oropharyngeal Pain 4 2
Cough 3 1
a CYMBALTA is not approved for the treatment of pediatric MDD [see Use In Specific Populations]. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.
b Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain.
cAlso includes asthenia.
dFrequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=467 CYMBALTA; N=354 Placebo).
e Also includes hypersomnia and sedation.
f Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia.

Other adverse reactions that occurred at an incidence of less than 2% and were reported by more CYMBALTA-treated patients than placebo-treated patients in pediatric MDD and GAD clinical trials included: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor (CYMBALTA is not approved to treat pediatric patients with MDD).

The most commonly reported symptoms following discontinuation of CYMBALTA in pediatric MDD and GAD clinical trials included headache, dizziness, insomnia, and abdominal pain [see WARNINGS AND PRECAUTIONS].

Growth (Height and Weight) in Pediatric Patients 7 to 17 Years Old with GAD and MDD

Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. CYMBALTA-treated pediatric patients in clinical trials experienced a 0.1 kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated pediatric patients. The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the CYMBALTA group than in the placebo group (16% and 6%, respectively). Subsequently, over the 4-to 6-month uncontrolled extension periods, CYMBALTA-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age-and sex-matched peers.

In studies up to 9 months, CYMBALTA-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in patients 7 to 11 years of age and 1.3 cm increase in patients 12 to 17 years of age). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in patients 7 to 11 years of age and increase of 0.3% in patients 12 to 17 years of age). Weight and height should be monitored regularly in pediatric patients treated with CYMBALTA [see Use In Specific Populations].

Adverse Reactions in Pediatric Patients Aged 13 to 17 Years Old with Fibromyalgia

Table 7 provides the incidence of adverse reactions in a fibromyalgia pediatric placebo-controlled trial (Study FM-4) that occurred in greater than 5% of patients treated with CYMBALTA and with an incidence greater than patients treated with placebo [see Clinical Studies].

Table 7: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in a 13-week Placebo-Controlled Trial in Pediatric Patients 13 to 17 Years Old with Fibromyalgia (Study FM-4)a

CYMBALTA
(N=91)
Placebo
(N=93)
Nausea 25% 15%
Decreased appetite 15% 3%
Vomiting 15% 5%
Decreased weightb 15% 5%
Headache 14% 11%
Nasopharyngitis 9% 2%
Somnolence 9% 3%
Upper respiratory tract infection 7% 2%
Viral gastroenteritis 5% 0%
Fatigue 5% 2%
a The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.
bFrequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=89 CYMBALTA; N=92 Placebo).

Postmarketing Experience

The following adverse reactions have been identified during post approval use of CYMBALTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally related to CYMBALTA therapy and not mentioned elsewhere in labeling include: acute pancreatitis, anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), extrapyramidal disorder, galactorrhea, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.

DRUG INTERACTIONS

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Inhibitors Of CYP1A2

When CYMBALTA 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see WARNINGS AND PRECAUTIONS].

Inhibitors Of CYP2D6

Concomitant use of CYMBALTA (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see WARNINGS AND PRECAUTIONS].

Dual Inhibition Of CYP1A2 And CYP2D6

Concomitant administration of CYMBALTA 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.

Drugs That Interfere With Hemostasis (E.g., NSAIDs, Aspirin, And Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with CYMBALTA 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUCτ,ss, Cmax,ss or tmax,ss) for both R-and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when CYMBALTA is initiated or discontinued [see WARNINGS AND PRECAUTIONS].

Lorazepam

Under steady-state conditions for CYMBALTA (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration.

Temazepam

Under steady-state conditions for CYMBALTA (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration.

Drugs That Affect Gastric Acidity

CYMBALTA has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, CYMBALTA, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using CYMBALTA in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of CYMBALTA with aluminum-and magnesium-containing antacids (51 mEq) or CYMBALTA with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral

Drugs Metabolized By CYP1A2

In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with CYMBALTA (60 mg twice daily).

Drugs Metabolized By CYP2D6

Duloxetine is a moderate inhibitor of CYP2D6. When CYMBALTA was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see WARNINGS AND PRECAUTIONS].

Drugs Metabolized By CYP2C9

Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine [see Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, And Warfarin)].

Drugs Metabolized By CYP3A

Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.

Drugs Metabolized by CYP2C19

Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.

Monoamine Oxidase Inhibitors (MAOIs)

[See DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS].

Serotonergic Drugs

[See DOSAGE AND ADMINISTRATION,CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS].

Alcohol

When CYMBALTA and ethanol were administered several hours apart so that peak concentrations of each would coincide, CYMBALTA did not increase the impairment of mental and motor skills caused by alcohol.

In the CYMBALTA clinical trials database, three CYMBALTA-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see WARNINGS AND PRECAUTIONS].

CNS Drugs

[See WARNINGS AND PRECAUTIONS].

Drugs Highly Bound To Plasma Protein

Because duloxetine is highly bound to plasma protein, administration of CYMBALTA to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of CYMBALTA (60 or 120 mg) with warfarin (2-9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) [see Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, And Warfarin)].

Drug Abuse And Dependence

Abuse

In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential.

While CYMBALTA has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of CYMBALTA (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Dependence

In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

Read the entire FDA prescribing information for Cymbalta (Duloxetine Hcl)

© Cymbalta Patient Information is supplied by Cerner Multum, Inc. and Cymbalta Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Health Solutions From Our Sponsors